Process for conversion of cyanopyridines to nicotinamides and catalyst therefor, process for preparing said catalyst

ABSTRACT

The present invention relates to an improved process for conversion of cyanopyridines to nicotinamides. More particularly the present invention relates to preparation of nicotinamides and isonicotinamides which finds its usage in the preparation of anti-TB drug i.e. isoniazid and as an intermediate of vitamin B 12 . The present invention also relates to a process for a catalyst useful for the preparation of nicotinamide and isonicotinamide.

FIELD OF THE INVENTION

The present invention relates to an improved process for conversion ofcyanopyridines to nicotinamides. More particularly the present inventionrelates to preparation of nicotinamides and isonicotinamides which findsits usage in the preparation of anti-TB drug i.e. isoniazid and as anintermediate of vitamin B₁₂. The present invention also relates to aprocess for a catalyst useful for the preparation of nicotinamide andisonicotinamide.

BACKGROUND OF THE INVENTION

Reference is made to Bull. Chem. Soc., Japan, Vol.-40, P-1660 (1967)wherein nickel oxide has been used as a catalyst for the hydration of3-cyanopyridine to nicotinamide. The drawbacks are that the catalyticactivity was reported to be low and the yield of nicotinamide was alsolow. Reference is also made to U.S. Pat. No. 4,008,241 to Gelbein et alof M/s. The Lummus Company (Bloom Field, N.J., USA) for the productionof nicotinamide from 3-cyanopyridine by aqueous ammonia solution. Thereaction temperature was 90-150° C., the reaction time was 4-8 hours andthe ammonia concentration was 3-8 molar. The maximum conversion of3-cyanopyridine was about 70%. The hydrolysis was also effected in thepresence of ammonium nicotinate in an amount sufficient to essentiallyeliminate production thereof to produce a hydrolysis effluent containingnicotinamide, ammonia, unconverted 3-cyanopyridine and ammoniumnicotinate, at a nicotinamide selectivity of essentially 100%. Further,in this process unconverted 3-cyanopyridine and ammonia were separatedfrom the product nicotinamide by a multi step separation process whichis not cost effective and is a very difficult procedure to get the pureproduct. These are the main drawbacks of the above process.

Prior art also discusses the hydration of nitrites to amides. Theconversion of nitrites to amides has been achieved by both chemical andbiological means. Japanese Patent 93-206579, August, 1993, H. Hirayama(To Showa Denko K.K., Japan), European Patent 85-306670, Sep., 19, 1985,S. Asano and J. Kitagawa (to Mitsui Toatsu Chemicals Inc.) describe theuse of modified Raney Nickel Catalyst for this reaction. WO 90/09988 A1,Sep., 17, 1990, of A. McKillop and D. Kemp. (to Interlex Chemicals,Ltd.) describes the use of alkali metal borates for this reaction. U.S.Pat. No. 2,471,518, May 31, 1949 (to Pyridium Company); U.S. Pat. No.4,721,709, Dec. 6, 1988 (to Standard Oil Company); German PatentApplication 2,517,054, Apr. 17, 1975, (to Degussa Company), discuss thehydrolysis of 3-cyanopyridine in presence of sodium hydroxide. The useof magnesium oxide catalyst for this reaction are discussed in ChemicalEngineering Science, 35, 330, 1975, by C. B. Rossa and G. B. Smith.Alkaline hydrolysis of 3-cyanopyridine to nicotinamide of the Degussaprocess is one of the most important commercial processes adopted bysome firms in India. However, this process has some disadvantages i.e.,the yield of nicotinamide is not very high and the conversion of3-cyanopyridine is about 99%. Reaction has been conducted at a higherreaction temperature with an appreciable alkali concentration. Nicotinicacid is also produced with nicotinamide in the above process.

U.S. Pat. No. 1,133,013; 1968, describe the catalytic hydration ofnitriles by manganese dioxide. Manganese dioxide has been prepared byRedox method using potassium permanganate and manganese sulphate inalkaline medium. The hydration of 3-cyanopyridine has been conductedusing catalyst: 3-cyanopyridine mole ratio as 2.16:1, and the yield isonly 79.28 mole %. The process i.e., conversion of 3-cyanopyridine tonicotinamide is similar to the conversion of 4-cyanopyridine toisonicotinamide. Manganese dioxide has been prepared by Redox methodusing potassium permanganate and manganese sulphate in alkaline medium.The main drawbacks of the process are that (a) the yield ofisonicotinamide is less (b) it is not eco-friendly and (c) the amount ofcatalyst per mole of the feed for conversion is quite high.

OBJECTS OF THE INVENTION

The main object of the invention is to provide an improved process forconversion of cyanopyridines to nicotinamides.

Another object of the invention is to provide a process for synthesis ofnicotinamide from 3-cyanopyridine and isonicotinamide from4-cyanopyridin using specially prepared Manganese Dioxide as thecatalyst which obviates the drawbacks as detailed above.

Yet another object of the invention is to use specially preparedmanganese dioxide catalyst of specific characteristics for the hydrationof 3- and 4-cyanopyridines to nicotinamide and isonicotinamiderespectively with highest conversion and selectivity.

SUMMARY OF THE INVENTION

Accordingly, the invention provides a process for conversion ofcyanopyridines to nicotinamides comprising dissolving the cyanopyridinein water; adding a transition metal catalyst prepared in neutral medium,refluxing the reaction mixture, cooling filtering and washing theresultant mixture and evaporating the filtrate to dryness to obtain theproduct.

In another embodiment of the invention, the refluxing temperature is inthe range of 100 to 115° C. and the refluxing time is in the range of 6to 15 hours.

In one embodiment of the invention, the amount of cyanopyridinedissolved in water is in the range of 0.8 to 2.0 moles for every 1.5 to8.0 moles of water and the transition metal oxide catalyst is added toin an amount in the range of 0.01 to 0.03 moles.

In another embodiment of the invention, the catalyst used is manganesedioxide.

In another embodiment of the invention, the manganese dioxide catalystis prepared by a Redox method using potassium permanganate and manganesechloride solution in neutral medium.

In another embodiment of the invention, the product nicotinamide is morethan 99% pure confirmed by melting point determination and by FTIRSpectroscopy.

The present invention also relates to a process for preparation of acatalyst useful for preparation of nicotinamide and isonicotinamidewhich comprises reacting potassium permanganate and manganous saltsolution in neutral medium by drop wise addition of aqueous solution ofmanganous salt to aqueous solution of potassium permanganate withconstant stirring, allowing the reaction mixture to stand, filtering theprecipitate of MnO₂ and washing with distilled water, drying theprecipitation to obtain the catalyst.

In one embodiment of the invention, the drop wise addition of aqueoussolution of manganous salt to aqueous solution of potassium permanganateis carried out at a temperature in the range of 30 to 80° C. and for atime period in range of 30 minutes to 1 hour.

In another embodiment of the invention, the reaction mixture is allowedto stand for a time period in the range of 10 to 15 hours.

In yet another embodiment of the invention, the precipitate of manganesedioxide is dried in an air oven at 110° C. for 3-4 hours.

In another embodiment of the invention, the manganous salt is selectedfrom manganese chloride and manganese sulphate.

DETAILED DESCRIPTION OF THE INVENTION

It is known to prepare solid oxide catalyst generally by for example, bycalcining the hydroxide, to convert it to the corresponding oxide. Thehydroxide can be formed in simplest embodiment, by means of normallyreferred to as precipitation. Such precipitation method comprises addingto an aqueous solution containing as dissolved therein water solubleinorganic or organic salts of manganese, for examples halide, nitrate,sulphate, formate, acetate, oxalate, water soluble basic substancepreferably an alkali metal hydroxide, carbonate or bicarbonate such asNaOH, KOH, Na₂ CO₃, NaHCO₃ and ammonium carbonate or bicarbonate tocause the precipitation of the hydroxide, filtering the resultinghydroxide, washing the remaining solid with water and drying theproduct.

The process steps for preparation of the catalyst consisting of Redoxmethod using an oxidising agent like KMnO₄ and a reducing agent likemanganous salt i.e. manganese chloride in neutral medium. While thecatalyst used in this invention can be prepared by any of theabove-described methods, a catalyst prepared by Redox method in neutralmedium is preferred.

Manganese dioxide catalyst has also been prepared by other methods i.e.heating Mn(NO₃)₂×H₂O, by reacting manganese acetate, sulphuric acid andpotassium persulphate. Manganese dioxide catalyst prepared by the Redoxmethod using potassium permanganate and manganese chloride in neutralmedium showed highest activity and selectivity in the hydration of 3-and 4-cyanopyridines to isonicotinamide. The purity of isonicotinamideis confirmed by determining its melting point and by FTIR Spectroscopy.The maximum yield of isonicotinamide achieved so far is 110-112% (wt.%)(90.2-91.8 mole %).

The present invention also provides a process for preparation of acatalyst useful for the conversion of 3- and 4-cyanopyridines tonicotinamide and isonicotinamide respectively which consists ofemploying Redox Method using potassium permanganate and manganesechloride solution in neutral medium. The process consists of drop wiseaddition of aqueous solution of manganese sulphate to aqueous solutionof potassium permanganate at a temperature in the range of 70 to 80° C.with constant stirring for a time period in the range of 30 minutes toone hour, left standing for a time period in the range of 10 to 15hours, filtering the precipitate of MnO₂ and washing with distilledwater until the filtrate become sulphate free, drying the precipitate inan air oven at 110° C. for three hours; dissolving the cyanopyridines(in the range of 0.8 to 2.0 moles) in water in the range of 1.5 to 8.0moles; addition of specially prepared manganese dioxide in the range of0.01 to 0.03 moles; refluxing the reaction mixture at a temperature inthe range of 100 to 115° C. for a time period in the range of 6 to 15hours; cooling, filtering and washing (with water) the resultant mixtureand evaporating the filtrate to dryness to obtain the product.

The manganese dioxide is preferably prepared by the Redox method usingpotassium permanganate and manganese chloride solution in neutralmedium. The catalyst so developed for the conversions is an inexpensive,water insoluble transition metal oxide particularly manganese dioxidecatalyst of specific characteristics due to generation of more hydroxylgroups characterized by the broad I.R. band in the region 3100-3600cm⁻¹. The separation of the catalyst from the hydration effluent is verymuch easier.

The product nicotinamide is more than 99% pure, the purity has beenconfirmed by melting point determination and also by analysing by FTIRSpectroscopy.

Mechanism of hydration using manganese dioxide catalyst is explained asfollows:

The role of manganese in the reaction has not yet been elucidated. Itmay be postulated that since the reaction is bi-phasic, adsorption ofthe substrate is followed by hydrolysis and subsequent desorption of theproduct. More easily hydrolysable compounds, are however, those thatwould be expected to form the most stable carbonium ion, which mayperhaps play an important role in the reaction mechanism. The peculiareffectiveness of manganese dioxide may in part be related to the factthat as ordinarily prepared by precipitation it is a‘non-stoichiometric’ compound, has oxygen content slightly less thanthat corresponding to the dioxide and also contains water (3-4%) whichcannot be removed thermally without further loss of Oxygen (J. T. Grey,J. Amer. Chem. Sec., 1946, 68, 605). The water is present probably ashydroxyl group linked to manganese. To confirm this statement, I.R ofdifferent samples of MnO₂ prepared by different methods were recordedand in some cases broad band in the region 3100-3600 cm⁻¹ were observedindicative of the present of hydroxyl groups. The formation ofhydroxylated intermediates may be assisted, if not caused, by thesehydroxyl groups in manganese dioxide resulting in the formation ofamides.

The novelty of the invention resides in preparing the catalyst manganesedioxide in neutral medium, having 100% selectivity, which is useful forthe conversion of 3- and 4-cyanopyridines to nicotinamide andisonicotinamide respectively without use of alkali or acid in comparisonto prior art catalysts, which necessitates an extremely complicated andcumbersome seperation procedure for the conversion. This catalysteliminates the formation of nicotinic acid in comparison to prior art.

The following examples are given by way of illustration and thereforeshould not be construed to limit the scope of the present invention.

EXAMPLE 1

125 ml of 0.471 molar aqueous solution of manganese sulphate was addeddrop wise to 150 ml of 0.395 molar aqueous solution of potassiumpermanganate at 80° C. with constant stirring for an hour and leftstanding for 15 hours. The precipitate of MnO₂ was filtered and washedwith distilled water until the filtrate become sulphate free. Theprecipitate was dried in an air oven at 1110° C. for three hours. Weightof manganese dioxide was observed to be 0.1497 mole.

0.096 mole of 3-cyanopyridine was dissolved in 5.556 mole of water and0.0115 mole of MnO₂, which prepared by above method, was added to this.The mixture was refluxed at 105° C. for 8 hrs. The reaction mixture wascooled and filtered. The filtrate was evaporated in dryness to get solidnicotinamide 0.095 mole. Yield of isonicotinamide was 98.9 mole %.

EXAMPLE 2

115 ml of 0.649 molar aqueous solution of potassium permanganate wasadded drop wise to 225 ml of 0.5 molar aqueous solution of manganesechloride at 70° C. temperature with vigorous stirring. Addition wascontinued for 1 hour and kept standing for 15 hours. The precipitate ofmanganese dioxide was filtered, washed with distilled water to makechloride ion free. The precipitate was put in an air oven at 110° C. for3 hours and weight of MnO₂ was 0.189 mole.

0.096 mole 3-cyanopyridine was dissolved in 4.55 mole of water and0.0115 mole of MnO₂ prepared by above method was added to this. Themixture was refluxed at 100° C. for 13.5 hrs. The reaction mixture ascooled and filtered. The filtrate was evaporated to dryness to get solidnicotinamide 0.0879 mole. Yield of nicotinamide was 91.56 mole %.

EXAMPLE 3

225 ml of 0.332 molar aqueous solution of potassium permanganate wasadded to 100 ml of 1.125 mole aqueous solution of manganese chloridewith continuous stirring at 30° C. The product manganese dioxide wasfiltered, washed with distilled water till free from chloride ions. Theprecipitated manganese dioxide was dried in an air oven at 1110° C. for4 hours. Weight of manganese dioxide was 0.23 mole.

0.096 mole of 3-cyanopyridine was dissolved in 5.556 mole water and0.0115 mole of manganese dioxide, which was prepared by above method,was added to this solution. The reaction mixture was stirred andrefluxed at 100° C. for 8 hours. Reaction mixture was cooled, filteredand washed with distilled water thoroughly. The filtrate was evaporatedon a steam bath to dryness. After drying the weight of nicotinamide was0.0957 mole equivalent to yield of 99.6 mole %.

Comparative Examples for Preparation of MnO₂ Using PotassiumPermanganate and Manganous Salt in Presence of Sodium Hydroxide.

EXAMPLE 4

300 ml of 0.303 molar aqueous solution of manganese chloride and 60 ml9.75 molar solution of sodium hydroxide was added simultaneously dropwise in the solution of 300 ml of 1.013 molar aqueous solution ofpotassium permanganate at 70° C. for an hour with constant stirring andkept standing for 12 hrs. The precipitate of manganese dioxide wasfiltered and washed with distilled water till free from chloride ions.The precipitate was dried at 110° C. for 8 hrs. Yield of manganesedioxide was 0.198 mole.

0.096 mole 4-cyanopyridine was dissolved in 5.556 mole water and 0.0115mole of manganese dioxide, which was prepared by above method, was addedto this. The reaction mixture was refluxed at 100° C. for 8 hrs. in aglycerine bath. The reaction mixture was cooled, filtered and washedthoroughly with distilled water. The filtrate was evaporated on steambath to dryness. Weight of isonicotinamide was 0.089 mole. Yield was92.71 mole %.

EXAMPLE 5

0.112 mole of Mn(NO₃). 6H₂O. was heated by 430° C. for 4 hrs in themuffle furnace 0.107 mole of MnO₂ was obtained. The yield of MnO₂ was95.5 mole %.

0.096 mole of 4-cyanopyridine was dissolved in 1.94 mole of water and0.0115 mole MnO₂, which was obtained by above method was added to thisand the reaction mixture was refluxed for 8 hours at 115° C. in an oilbath. The reaction mixture was extracted with organic solvent (CCI₄).Aqueous layer was evaporated to dryness and yield of isonicotinamide was0.0082 mole. Unreacted 4-cyanopyridine was 0.048 mole. Yield ofisonicotinamide was 8.5 mole %.

EXAMPLE 6

270 ml of 0.332 molar aqueous solution of MnSO₄.4H₂O and 117 ml 10.0molar aqueous solution of sodium hydroxide were added drop wisesimultaneously with constant stirring to hot (at 70° C.) 600 ml of1.0123 molar aqueous solution of KMnO₄. After addition of MnSO₄.4H₂O andsodium hydroxide solution the whole mass was stirred and heated again at70° C. for 90 minutes. It was kept for settling for 12 hrs. It wasfiltered and the precipitate was washed several times with distilledwater until the precipitate was free from SO₄ ⁻² and OH ions. Theprecipitate was dried in an air oven at 110° C. till constant weight.The yield of MnO₂ was 0.314 mole.

0.1923 mole 3-cyanopyridine was dissolved in 7.778 mole of water and0.023 mole manganese dioxide, which was prepared by above method, wasadded to this solution. The mixture was refluxed at 100° C. for 8 hrs ina glycerine bath. The reaction mixture was cooled, filtered and washedwith distilled water. The filtrate was evaporated on steam bath todryness. Weight of nicotinamide was 0.165 mole and yield was 85.0 mole%.

The Main Advantages of the Present Invention are:

-   1. Nicotinamide can be produced by catalytic hydration of    3-cyanopyridine without use of alkali or acid as prior art catalyst,    which necessitates an extremely complicated and cumbersome    separation procedure for the product nicotinamide.-   2. The catalyst hydrated manganese dioxide has been prepared by the    Redox method using potassium permanganate and manganese chloride    solution in neutral medium.-   3. The catalyst used in the present invention eliminates the    formation of nicotinic acid which is produced in substantial amount    using the prior art catalysts (acid or alkali).-   4. The yield of nicotinamide is 91.8 mole % and the selectivity is    100% which is much higher than the catalyst report so far.-   5. The process also provides for easy and economic recovery of    nicotinamide from the resulting hydrolysis effluents.

1-9. (canceled)
 10. A process for preparation of a catalyst useful forpreparation of nicotinamide and isonicotinamide which comprises reactingpotassium permanganate and manganous salt solution in neutral medium bydrop wise addition of aqueous solution of manganous salt to aqueoussolution of potassium permanganate with constant stirring, allowing thereaction mixture to sand, filtering the precipitate of MnO₂ and washingwith distilled water, drying the precipitation to obtain the catalyst.11. A process as claimed in claim 10, wherein dropwise addition ofaqueous solution of manganous salt to aqueous solution of potassiumpermanganate is carried out at temperature in range of 30 to 80° C. andfor a time period in range of 30 minutes to 1 hour.
 12. A process asclaimed in claim 10 wherein the reaction mixture is allowed to stand fora time period in the range of 10 to 15 hours.
 13. A process as claimedin claim 10 wherein the precipitate of manganese dioxide is dried in anair oven at 110° C. for 3-4 hours.
 14. A process as claimed in claim 10wherein the manganous salt is selected from manganese chloride andmanganese sulphate.